We propose a "two-hit" working model to guide our research on the etiology of schizophrenia. The first proposed hit consists of a disruption of fetal neural development induced by genetic or teratogenic factors. The second hit may take the form of 1) brain damage caused by delivery complications or 2) stressful, non-optimal rearing circumstances. The nature of the second hit may determine the course of illness. We plan to test this working model in three projects: Project 1. 1962 High Risk Project. This project has followed a sample of 311 children of schizophrenic mothers and controls for the past 33 years. We have descriptions of the lives and the biological and social characteristics for each of the individuals. Of the 311, 33 have become schizophrenic. We propose to examine this data bank to attempt to understand what combination of characteristics and events is associated with schizophrenic outcome. Project 2. Fetal Virus Project. We have recently found that genetic predisposition and teratogenic factors, the two first hits, seem to be associated with different clinical outcomes within the schizophrenia diagnostic umbrella. We propose to replicate this finding in a larger population to differentiate effects of genetic vs. teratogenic factors. Project 3. Perinatal Disturbance and Adult Schizophrenia. We have been following a Danish Perinatal Cohort of 9,125 consecutive deliveries. We have ascertained their adult psychiatric status. In two studies we have noted that: 1) early institutional rearing and 2) delivery complications predict to schizophrenia among those at genetic risk (with schizophrenic parents).